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  • Journal article
    Davis SPX, Kumar S, Alexandrov Y, Bhargava A, da Silva Xavier G, Rutter GA, Frankel P, Sahai E, Flaxman S, French PMW, McGinty Jet al., 2019,

    Convolutional neural networks for reconstruction of undersampled optical projection tomography data applied to in vivo imaging of zebrafish.

    , Journal of Biophotonics, Vol: 12, ISSN: 1864-063X

    Optical projection tomography (OPT) is a 3D mesoscopic imaging modality that can utilize absorption or fluorescence contrast. 3D images can be rapidly reconstructed from tomographic data sets sampled with sufficient numbers of projection angles using the Radon transform, as is typically implemented with optically cleared samples of the mm-to-cm scale. For in vivo imaging, considerations of phototoxicity and the need to maintain animals under anesthesia typically preclude the acquisition of OPT data at a sufficient number of angles to avoid artifacts in the reconstructed images. For sparse samples, this can be addressed with iterative algorithms to reconstruct 3D images from undersampled OPT data, but the data processing times present a significant challenge for studies imaging multiple animals. We show here that convolutional neural networks (CNN) can be used in place of iterative algorithms to remove artifacts - reducing processing time for an undersampled in vivo zebrafish dataset from 77 to 15 minutes. We also show that using CNN produces reconstructions of equivalent quality to CS with 40% fewer projections. We further show that diverse training data classes, for example ex vivo mouse tissue data, can be used for CNN-based reconstructions of OPT data of other species including live zebrafish.

  • Journal article
    Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Krentz NAJ, Kleiner S, Jain D, Richard A-M, Abaitua F, Beer NL, Grotz A, Prasad RB, Hansson O, Ahlqvist E, Krus U, Artner I, Suoranta A, Gomez D, Baras A, Champon B, Payne AJ, Moralli D, Thomsen SK, Kramer P, Spiliotis I, Ramracheya R, Chabosseau P, Theodoulou A, Cheung R, van de Bunt M, Flannick J, Trombetta M, Bonora E, Wolheim CB, Sarelin L, Bonadonna RC, Rorsman P, Davies B, Brosnan J, McCarthy MI, Otonkoski T, Lagerstedt JO, Rutter GA, Gromada J, Gloyn AL, Tuomi T, Groop Let al., 2019,

    Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

    , Nature Genetics, Vol: 51, Pages: 1596-1606, ISSN: 1061-4036

    A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

  • Conference paper
    Marselli L, Suleiman M, Colli ML, Pocai A, Burdet F, Turatsinze J-V, Steinmeyer K, Thorens B, Schulte AM, Ibberson M, Rutter GA, Norquay L, Eizirik DL, Cnop M, Marchetti Pet al., 2019,

    The transcriptome of persistent or transient human beta cell dysfunction caused by lipo-glucotoxicity correlates with the gene expression signature of type 2 diabetic islets

    , 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S167-S167, ISSN: 0012-186X
  • Conference paper
    Bitsi S, Buenaventura T, Laughlin WE, Burgoyne T, Lyu Z, Grimes J, Koszegi Z, Calebiro D, Rutter GA, Bloom SR, Jones B, Tomas Aet al., 2019,

    GLP-1R translocation to plasma membrane nanodomains and downstream signalling are modulated by agonist-dependent receptor palmitoylation

    , 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S215-S215, ISSN: 0012-186X
  • Journal article
    Jaafar R, Tran S, Shah A, Sun G, Valdearcos M, Marchetti P, Masini M, Swisa A, Giacometti S, Bernal-Mizrachi E, Matveyenko A, Hebrok M, Dor Y, Rutter GA, Koliwad SK, Bhushan Aet al., 2019,

    mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.

    , Journal of Clinical Investigation, Vol: 130, Pages: 4124-4137, ISSN: 0021-9738

    Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.

  • Journal article
    Buenaventura T, Bitsi S, Laughlin WE, Burgoyne T, Lyu Z, Oqua AI, Norman H, McGlone ER, Klymchenko AS, Corrêa IR, Walker A, Inoue A, Hanyaloglu A, Grimes J, Koszegi Z, Calebiro D, Rutter GA, Bloom SR, Jones B, Tomas A, Buenaventura T, Bitsi S, Laughlin W, Burgoyne T, Lyu Z, Oqua A, Norman H, McGlone E, Klymchenko A, Corrêa Jr I, Walker A, Inoue A, Hanyaloglu A, Grimes J, Koszegi Z, Calebiro D, Rutter G, Bloom S, Jones B, Tomas Catala Aet al., 2019,

    Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.

    , PLoS Biology, Vol: 17, Pages: 1-40, ISSN: 1544-9173

    The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

  • Journal article
    Da Silva Xavier G, Rutter GA, 2019,

    Metabolic and Functional Heterogeneity in Pancreatic β Cells.

    , J Mol Biol

    Metabolic and secretory heterogeneity are fundamental properties of pancreatic islet β cells. Emerging data suggest that stable differences in the transcriptome and proteome of individual cells may create cellular hierarchies, which, in turn, establish coordinated functional networks. These networks appear to govern the secretory activity of the whole islet and be affected in some forms of diabetes mellitus. Functional imaging, for example, of intracellular calcium dynamics, has led to the demonstration of "small worlds" behavior, and the identification of highly connected "hub" (or "leader") cells and of follower populations subservient to them. Subsequent inactivation of members of either population, for example, using optogenetic approaches or photoablation, has confirmed the importance of hub cells as possible pacemakers. Hub cells appear to be enriched for the glucose phosphorylating enzyme glucokinase and for genes encoding other enzymes involved in glucose metabolism compared to follower cells. Recent findings have shown the relevance of cellular hierarchy in islets from multiple species including human, mouse and fish, and shown that it is preserved in vivo in the context of the fully vascularized and innervated islet. Importantly, connectivity is impaired by insults, which mimic the diabetic milieu, including high glucose and/or fatty levels, and by the ablation of genes associated with type 2 diabetes risk in genome-wide association studies. We discuss here the evidence for the existence of these networks and their failure in disease settings. We also briefly survey the challenges in understanding their properties.

  • Conference paper
    Sposito T, Tu M-SN, Rutter GA, Novelli M, Thirlwell C, Salomoni Pet al., 2019,

    The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas

    , Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
  • Journal article
    Salem V, Delgadillo Silva L, Suba K, Mousavy Gharavy SN, Akhtar N, Martin-Alonso A, Gaboriau DCA, Rothery SM, Styliandes T, Carrat G, Pullen TJ, Pal Singh S, Hodson DJ, Leclerc I, Shapiro AMJ, Marchetti P, Briant LB, Distaso W, Ninov N, Rutter Get al., 2019,

    Leader β cells coordinate Ca2+ dynamics across pancreatic islets in vivo

    , Nature Metabolism, Vol: 1, Pages: 615-629, ISSN: 2522-5812

    Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected ‘hub’ cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.

  • Journal article
    Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, Engelhardt KR, Xu X, Chen R, Alvarez L, Berlinguer-Palmini R, Bull KR, Cawthorne E, Cribbs AP, Crockford TL, Dang TS, Fearn A, Fenech EJ, de Jong SJ, Lagerholm BC, Ma CS, Sims D, van den Berg B, Xu Y, Cant AJ, Kleiner G, Leahy TR, de la Morena MT, Puck JM, Shapiro RS, van der Burg M, Chapman JR, Christianson JC, Davies B, McGrath JA, Przyborski S, Santibanez Koref M, Tangye SG, Werner A, Rutter GA, Padilla-Parra S, Casanova J-L, Cornall RJ, Conley ME, Hambleton Set al., 2019,

    An essential role for the Zn2+ transporter ZIP7 in B cell development

    , Nature Immunology, Vol: 20, Pages: 350-361, ISSN: 1529-2908

    Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

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